Together, these results suggest that Hri deficiency may lead to spontaneous accumulation of α-synuclein aggregates in the central nervous system in aged mice, specifically along the lateral collateral pathway that is known to be impaired in α-synucleinopathies in humans (34), supporting the notion that HRI-dependent pathways contribute to the clearance of potentially cytotoxic protein aggregates. Here, SNCA is linked to synucleinopathy.